Opioids and opiates are potent analgesics widely used in clinical practice. Opioid and opiates drugs are classified typically by their binding selectivity in respect of the cellular and differentiated tissue receptors to which specific drug specie binds as a ligand. These receptors include mu (μ), delta (δ), kappa (κ) and the nociceptive receptors.
The well-known narcotic opiates, such as morphine and its analogues, are selective for the opioid mu receptors. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. However, despite their good activity as analgesics, opioids and opiates have the drawback of causing dependence.
Sigma receptors are non-opiaceous type of receptors of great interest in pharmacology due to their role in analgesia related processes. The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol. The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (σ-1) site, and has micromolar affinity for the sigma 2 (σ-2) site. Haloperidol has similar affinities for both subtypes.
It has been reported that some sigma ligands in combination with opioids or opiates are capable of modulating the analgesic effect thereof. It is known, for example, that haloperidol potentiates the activity of different opioids and opiates such as morphine, DADL or bremazocine [Chichenkov, O. N. et al: Effect of haloperidol on the analgesic activity of intracisternally and intrathecally injected opiate agonists, Farmakologiya i Toksikologiya (Moscow) (1985), 48(4), 58-61]. Chien C. et al also referred the synergistic effect of the combination of haloperidol and morphine [Selective antagonism of opioid analgesia by a sigma system, J Pharmacol Exp Ther (1994), 271, 1583-1590 and Sigma antagonists potentiate opioid analgesia in rats, Neurosci Lett (1995), 190, 137-139] and Marazzo A. et al taught the capacity of the sigma ligand (+)-MR200 to modulate κ-opioid receptor mediated analgesia. Mei J. et al confirmed the importance of sigma-1 receptors as a modulatory system on the analgesic activity of opioid drugs [Sigma1 receptor modulation of opioid analgesia in the mouse, J Pharmacol Exp Ther (2002), 300(3), 1070-1074]. Notwithstanding, in all of this cases the problem of dependence induced by opioids and opiates remain to be present.
One of the pharmacological approaches to solve the problem of opioid and opiate dependency has been the co-administration of opioids or opiates and sigma ligands. For instance, sigma-1 receptor agonist SA4503 has been shown to have a modulatory effect on addiction to morphine [Nomura, M. et al: Studies on drug dependence (Rept. 322) : Attenuation of morphine- and psychostimulants-induced place preference by sigmal receptor agonist SA4503, 72nd Annual Meeting of the Japanese Pharmacological Society (Sapporo, Japan-March 1999)]. Also, sigma-1 agonist DHEA has shown some capacity to attenuate the development of morphine dependence [Noda, Y. et al: A neuroactive steroid, dehydroepiandrosterone sulfate, attenuates the development of morphine dependence: an association with sigma1 receptors, 31st Annual Meeting of the Society of Neuroscience (San Diego-November 2001)]. EP1130018 teaches the use of sigma ligands for the treatment of drug addiction to morphine, cocaine and methamphetamine. However, none of these approaches show an enhancement of the analgesic effect of morphine.
Therefore, it is desirable to find sigma ligands capable of synergistically potentiate the analgesic effect of opioids or opiates while attenuating at the same time the dependency thereof.